Thick and Thin Filament Gene Mutations in Striated Muscle Diseases

Int. J. Mol. Sci. 2008, 9, 1259-1275; DOI: 10.3390/ijms9071259 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.org/ijms/ Review Thick and Thin Filament Gene Mutations in Striated Muscle Diseases Homa Tajsharghi Department of Pathology, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden Tel.: +46-31-3422343; Fax: +46-31-417283; E-Mail: [email protected] Received: 8 May 2008; in revised form: 23 May 2008 / Accepted: 12 June 2008 / Published: 16 July 2008 Abstract: The sarcomere is the fundamental unit of cardiac and skeletal muscle contraction. During the last ten years, there has been growing awareness of the etiology of skeletal and cardiac muscle diseases originating in the sarcomere, an important evolving field. Many sarcomeric diseases affect newborn children, i. e. are congenital myopathies. The discovery and characterization of several myopathies caused by mutations in myosin heavy chain genes, coding for the major component of skeletal muscle thick filaments, has led to the introduction of a new entity in the field of neuromuscular disorders: myosin myopathies. Recently, mutations in genes coding for skeletal muscle thin filaments, associated with various clinical features, have been identified. These mutations evoke distinct structural changes within the sarcomeric thin filament. Current knowledge regarding contractile protein dysfunction as it relates to disease pathogenesis has failed to decipher the mechanistic links between mutations identified in sarcomeric proteins and skeletal myopathies, which will no doubt require an integrated physiological approach. The discovery of additional genes associated with myopathies and the elucidation of the molecular mechanisms of pathogenesis will lead to improved and more accurate diagnosis, including prenatally, and to enhanced potential for prognosis, genetic counseling and developing possible treatments for these diseases. The goal of this review is to present recent progress in the identification of gene mutations from each of the major structural components of the sarcomere, the thick and thin filaments, related to skeletal muscle disease. The genetics and clinical manifestations of these disorders will be discussed. Keywords: sarcomere, myosin, myosin heavy chain, actin, myopathy, myosin myopathy Int. J. Mol. Sci. 2008, 9 1260 1. Introduction During the past decade, major advances have been made in defining the molecular basis of many genetically transmitted diseases. During this period, there has been growing awareness of the importance of sarcomeric protein mutations in the etiology of myopathy. Numerous mutations are currently associated with myopathy, with remarkable spectrum of phenotypic variation. In addition to a better understanding of the primary defect and basic molecular pathogenesis of disease, redefining the diagnostics of many disorders is another benefit of identifying the disease genes. These fundamental approaches will allow us to understand why a point mutation at one site in a sarcomeric protein (e.g. tropomyosin (TM)) leads to nemaline myopathy (NM), while a different point mutation causes distal arthrogryposis (DA). Improved understanding of the molecular basis of disease will probably allow targeting of pharmacological strategies as well as providing the cornerstone for gene therapy approaches. In this review, disorders caused by mutation of sarcomeric thick and thin filament proteins will be discussed. 2. The Sarcomere The sarcomere represents the basic contractile unit of both skeletal and cardiac muscle. It is a highly ordered structure composed of the thin and thick filaments, titin, and nebuline [1]. The characteristic striated appearance of muscle fibers is observable by electron microscopy as alternating light (I) and dark (A) bands (Figure 1). The principle components of striated muscle sarcomeres include parallel arrays of actin-containing thin filaments that span the I-band and overlap with myosin-containing thick filaments in the A-band. The thin filaments are anchored in the Z-disc and the thick filaments are similarly anchored in the M-band [1]. Figure 1. a) Ultrastructurally, the A-band corresponds to the thick filaments and includes a zone where the thin filaments overlap the thick filaments. The I-band is the zone in which the thin filaments do not overlap the thick filaments. The Z-line is a dark band in the centre of the I-band and the M-line runs down the center of the A-band. Int. J. Mol. Sci. 2008, 9 1261 Skeletal muscle function depends on a precise alignment of actin and myosin filaments. This is achieved by accessory proteins, such as α-actinin, myomesin, M-protein, titin, desmin and myosin- binding proteins (MyBP)-C and -H, which link the different components and keep them aligned with each other [1] (Figure 2). The major component of the Z-line is α-actinin, which acts as an actin cross- linking protein and holds actin filaments in a lattice arrangement in the Z-disc [2, 3]. It has been proposed that myomesin and M-protein may connect titin and myosin filament systems and that myomesin plays a role in integrating thick filaments into assembling sarcomeres [4]. Titin, a huge protein which runs parallel to the filament array, forms a continuous filament system in myofibrils [1]. Desmin is the predominant intermediate filament protein of striated muscle [5] and contributes to maintaining the integrity and alignment of myofibrils [1]. MyBP-C is localized in seven stripes running parallel to the M-band (Figure 2). Because MyBP-C interacts with both the thick and titin filaments, its function may be to link them together and/or to align the thick filaments in the A-band [1]. In addition, MyBP-C reduces the critical concentration for myosin polymerization and the resulting filaments are longer and more uniform in length than those polymerized in its absence [6, 7]. Both myosin-binding proteins appear to aid in the assembly of vertebrate muscle thick filaments into their precise lengths [1]. It has also been suggested that MyBP-C and –H may be involved in regulating muscle contraction [8]. Figure 2. Illustration of the I-band, A-band, and M-line regions of the sarcomere. The thin filaments contain actin, tropomyosin, troponins C, I, and T and nebulin. The thick filaments are composed of myosin with the globular heads forming cross-bridges with thin filaments. Myosin-binding proteins, including MyBP-C, are associated with the thick filaments. The giant protein titin extend the length of an entire half sarcomere. The M-line contains different proteins, such as myomesin and M-protein. 2.1. The Major Component of the Thick Filament: Myosin Contraction of muscle is the result of cyclic interactions between the globular heads of the myosin molecules, also known as cross-bridges, and the actin filaments. The repetitive binding and release results in sliding of the thick filaments along the thin filaments powered by the hydrolysis of ATP. Myosin can be regarded as an ATPase that is activated by the binding of actin [9]. Myosin acts as a molecular motor that converts the chemical energy of ATP hydrolysis into mechanical force in eukaryotic cells [10]. Conventional myosin exists as a hexameric protein Int. J. Mol. Sci. 2008, 9 1262 composed of two myosin heavy chain (MyHC) subunits and two pairs of non-identical light chain (MyLC) subunits (Figure 3). The MyHC has two functional domains. The globular, amino-terminal head domain, to which MyLCs bind, exhibits the motor function. The elongated alpha-helical coiled- coil carboxyl-terminal rod domain exhibits filament-forming properties [10]. The globular head that forms the cross-bridges contains the binding sites for actin and ATP [11]. Figure 3. Schematic illustration of a myosin class II molecule, showing the essential light chains (ELC) and regulatory light chains (RLC) that wrap around the α-helical region of the S1. Two MyHC molecules intertwine via their α-helical regions to form a coiled-coil rod. Proteolytic fragments S1, S2 and LMM are indicated. The MyHC can be cleaved by proteolytic enzymes into two subfragments, heavy meromyosin (HMM) and light meromyosin (LMM) [12, 13]. The HMM contains the head region, termed subfragment 1 (S1), and a portion of the coiled-coil-forming sequence referred to as subfragment 2 (S2) which connects the myosin heads to the thick filament. The LMM is the C-terminal proportion of the rod, which lies along the thick filAMent axis [14] (Figure 3). The myosin motor domain is essentially constructed of three domains connected by flexible linkers. The 25-kDa amino-terminal nucleotide-binding domain is connected to the upper 50 kDa subdomain which is, in turn, connected to the lower 50-kDa subdomain. The third, 20-kDa domain is called the converter region (Figure 4). A long helix emerges from the converter domain and serves as the binding site for MyLCs. The essential light chains (ELC) occupy the binding site closest to the converter domain while the regulatory light chains (RLC) occupy the second site [15]. The binding sites are highly specific for their respective MyLCs [14]. The elongated neck region in S1 has been suggested to act as a lever arm to amplify small changes in the configuration of the motor domain into much larger displacements of actin [15]. Six striated muscle MyHCs are encoded by genes found in a tightly linked cluster on human chromosome 17 [16, 17]. The genes are arranged in the following order: MYH3, MYH2, MYH1, MYH8, MYH13 and MYH4 [18]. Cardiac MyHC isoforms encoded by MYH7 and MYH6 are located on chromosome 14 [19]. Three major MyHC isoforms are present in adult human limb muscle tissue: MyHC I, also called slow/beta MyHC (encoded by MYH7) is expressed in slow, type 1 muscle fibers and in heart ventricles; MyHC IIa (encoded by MYH2) is expressed in fast, type 2A muscle fibers and MyHC IIx Int. J. Mol. Sci. 2008, 9 1263 (encoded by MYH1) is expressed in fast, type 2B muscle fibers [20].

Load more